Iclaprim (MTF-100, which is also known as AR-100) is a potent inhibitor of microbial dihydrofolate reductase (DHFR) that is used to treat subjects with, for example, acute bacterial skin, skin structure infections (ABSSSI) and/or hospital-acquired bacterial pneumonia (HABP). Iclaprim is a targeted Gram-positive broad-spectrum bactericidal antibiotic, which has a low propensity for resistance development. Iclaprim also exhibits an alternative mechanism of action against bacterial pathogens, including Gram-positive isolates of many staphylococcal, streptococcal, and enterococcal genera, as well as various Gram-positive pathogens that are resistant to antibiotic treatment; e.g., methicillin-resistant Staphylococcus aureus (MRSA). Iclaprim thus has the potential to be an effective drug for treating infections of bacteria that have become resistant to standard antibiotics.
Iclaprim has characteristics that, to date, have prevented it from being approved for clinical use in humans. For example, IV administration of iclaprim can potentially cause QTc prolongation in a dose-dependent manner. However, dosing of iclaprim at levels which do not produce a cardiac safety signal have not shown satisfactory clinical efficacy. In particular, Phase III clinical trials (ASSIST-1 and ASSIST-2 studies) evaluating the intravenous administration of a weight-based dose of iclaprim below that which caused QTc prolongation did not achieve satisfactory efficacy profiles, based on the non-inferiority margin of −10% as set by the Food and Drug Administration (FDA), including the failure to achieve an optimal ratio of AUC to minimum inhibitory concentration (“MIC”) (AUC/MIC), time above the MIC (T>MIC) and steady-state maximal blood concentration (Cmax(ss)). See e.g., Morgan et al., Iclaprim: a novel dihydrofolate reductase inhibitor for skin and soft tissue infections, Future Microbiology, March 2009, Vol. 4, No. 2, Pages 131-144.
Accordingly, there is a need for safe and effective therapeutic methods for intravenous administration of iclaprim for treating bacterial infection.